The present invention relates to a novel method for producing a cyclic pentapeptide having a xcex2-turn and a xcex3-turn, cyclic pentapetides having a xcex2-turn and a xcex3-turn and use thereof.
The xcex2-turn and the xcex3-turn are known as one of regular structures of proteins or peptide molecules, and have structures bending at 4- and 3-amino acid residues, respectively. Usually, the xcex2-turn forms a hydrogen bond between carbonyl oxygen in the i-position and an amide proton in the i+3-position, and is classified into type I and type II according to two dihedral angles xcfx86 and "psgr" of the i+1-position and the i+2-position. The xcex3-turn forms a hydrogen bond between the i-position and the i+2-position. Such turn structures relates to intermolecular recognition and molecular interaction in many cases, because of their projected structures from molecular surfaces. With recent developments of X-ray crystal structure analysis and NMR analysis, three-dimensional structures of many biologically active peptides have been determined. Examples of peptides containing xcex2-turns in active sites include enkephalin [T. S. Sudha and P. Balaram, Int. J. Pept. Protein Res., 21(4), 381-388 (1983), and M. Goodman et al., Biopolymers, 26 (Suppl.), S25-S32 (1987)] and somatostatin [U. Nagai et al., Pept.: Chem. Biol., Proc. Am. Pept. Symp. 10th, 129-130 (1988)]. Attempts have further been made to imitate the xcex2-turn portions with non-peptide compounds [J. B. Ball and P. F. Alewood, J. Mol. Recognit., 3(2), 55-64 (1990), and G. L. Olson et al., J. Am. Chem. Soc., 112(1), 323-333 (1990)]. It has also been reported that RGD(Arg-Gly-Asp)- related peptides having vitronectin-sensitive cell adhesion activity have xcex3-turns in adhesion sites [G. Muler et al., Angew. Chem. Int. Ed. Enql., 31(3), 326-328 (1992)]. Recently, cyclic pentapeptide BQ123 was reported as an antagonist against endothelin by Banyu Pharmaceutical Co., Ltd. (U.S. Pat. No. 5,114,918) but it does not describe its conformation. Further, a specific cyclic pentapeptide as an endothelin receptor-antagonist or as an endothelin-antagonist, respectively has been reported to have a xcex2-turn and a xcex3-turn [R. A. Atkinson and J. T. Pelton, FEBS Lett., 296(1), 1-6 (1992), and S. R. Krystek Jr. et al., FEBS Lett., 299(3), 255-261 (1992)]. This is considered to be a three-dimensional structure inherent in the specific amino acid sequence of that specific cyclic pentapeptide.
A method for synthesizing peptides having a xcex2-turn followed by a xcex3-turn or a xcex3-turn followed by a xcex2-turn, can contribute to the development of drugs. Further, methods for introducing desired amino acid residues into the sites for the xcex2- and xcex3-turns can facilitate effective designing of compounds having biological activity.
The present inventors synthesized various cyclic pentapeptides and conducted intensive investigations of the conformations thereof. As a result, the present inventors discovered a novel manufacturing method by which compounds having xcex2- and xcex3-turns could be synthesized at will, regardless of residues.
The present invention directs to a novel method for forming xcex2- and xcex3-turns, only by controlling optical activity of a main chain of a cyclic pentapeptide, regardless of the kind of residues, a cyclic pentapeptide having xcex2- and xcex3-turns and use thereof.
Namely, the present invention provides (1) A cyclic pentapeptide having a xcex3-turn and a xcex2-turn wherein the cyclic pentapeptide has the following formula (I):
Cyclo(xe2x80x94A1xe2x80x94A2xe2x80x94A3xe2x80x94A4xe2x80x94A5xe2x80x94)xe2x80x83xe2x80x83(I)
wherein A1, A2, A3, A4 and A5 are amino acid residues;
said pentapeptide comprising amino acid residues in positions 1-2-3 to form a xcex3-turn, and amino acid residues in positions 3-4-5-1 to form a xcex2-turn in combination with the xcex3-turn;
in which D-xcex1-amino acid residues are selected for A1, A3 and A5 and L-xcex1-amino acid residues are selected for A2 and A4 or L-xcex1-amino acid residues are selected for A1, A3 and A5 and D-xcex1-amino acid residues are selected for A2 and A4;
(2) the cyclic pentapeptide of (1), in which A1, A3 and A5 are D-xcex1-amino acid residues, and A2 and A4 are L-xcex1-amino acid residues, with the proviso that when A1 is D-Asp, A3 is D-Val, A4 is L-Leu and A5 is D-Trp, A2 is L-amino acid other than L-Pro; (3) the cyclic pentapeptide of (2), in which A1 is D-alanine, D-valine, D-norvaline, D-leucine, D-norleucine, D-isoleucine, D-alloisoleucine, D-phenyl-alanine, D-tyrosine, D-tryptophan, D-serine, D-threonine, D-ornithine, D-lysine, D-arginine, D-histidine or D-methionine; A2 is an L-xcex1-amino acid; A3 is a D-xcex1-amino acid; A4 is an L-xcex1-amino acid; and A5 is D-xcex1-amino acid; (4) the cyclic pentapeptide of (2), in which A1 is D-aspartic acid, D-glutamic acid or D-cysteic acid; A2 is an L-xcex1-amino acid; A3 is a D-xcex1-amino acid; A4 is an L-xcex1-amino acid; and A5 is D-valine, D-norvaline, D-leucine, D-norleucine, D-isoleucine, D-alloisoleucine, D-serine, D-threonine, D-aspartic acid, D-glutamic acid, D-ornithine, D-lysine, D-arginine, D-histidine, D-methionine or D-cysteine; (5) the cyclic pentapeptide of (2), in which A1 is D-aspartic acid, D-glutamic acid or D-cysteic acid; A2 is an L-xcex1-amino acid; A3 is D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-aspartic acid, D-glutamic acid, D-ornithine, D-lysine, D-arginine, D-histidine, D-methionine or D-cysteine; A4 is an L-xcex1-amino acid; and A5 is D-phenylalanine, D-tyrosine, D-alanine or D-tryptophan; (6) the cyclic pentapeptide of (1), in which A1, A3 and A5 are L-xcex1-amino acid residues, and A2 and A4 are D-xcex1-amino acid residues; (7) the cyclic pentapeptide of (1), in which A1 is a D-xcex1-amino acid; A2 is an L-xcex1-amino acid having a protective group for the amino acid; A3 is a D-xcex1-amino acid; A4 is an L-xcex1-amino acid; and A5 is a D-xcex1-amino acid; (8) the cyclic pentapeptide of (7), in which a protective group is hydrophobic; (9) the cyclic pentapeptide of (8), in which a protective group is benzyl; (10) the cyclic pentapeptide of (7) is cyclo(-D-Glu-Ser(Bzl)-D-Leu-Leu-D-Trp); (11) the cyclic pentapeptide of (7) is cyclo(-D-Glu-Thr(Bzl)-D-Leu-Leu-D-Trp); (12) an NK2 receptor antagonist composition comprising any one of the cyclic pentapeptides of (1) to (11) and pharmaceutically acceptable carrier; (13) the composition of (12), in which said antagonist is an antiasthmatic agent, an anti-inflammatory agent or an antarthritic agent; (14) a method for producing a cyclic pentapeptide having a xcex3-turn and a xcex2-turn wherein the cyclic pentapeptide has the following formula (I):
Cyclo(xe2x80x94A1xe2x80x94A2xe2x80x94A3xe2x80x94A4xe2x80x94A5xe2x80x94)xe2x80x83xe2x80x83(I)
wherein A1, A2, A3, A4 and A5 are amino acid residues;
said method comprising selecting and reacting amino acid residues in positions 1-2-3 to form a xcex3-turn, and selecting and reacting amino acid residues in positions 3-4-5-1 to form a xcex2-turn in combination with the xcex3-turn;
in which D-xcex1-amino acid residues are selected for A1, A3 and A5 and L-xcex1-amino acid residues are selected for A2 and A4 or L-xcex1-amino acid residues are selected for A1, A3 and A5 and D-xcex1-amino acid residues are selected for A2 and A4;
(15) the method of (14), further comprising condensing two kinds of fragments to form a linear pentapeptide, and then cyclizing resulting linear pentapeptide to form the cyclic pentapeptide; and (16) a method of treating mammalian asthma, inflammation or arthritis which comprises administering to said mammal a pharmaceutical composition comprising an effective amount of any one of the cyclic pentapeptides of claim 1 to 11.